8-(3-amino-piperidin-1-yl)-7-(but-2-ynyl)-xanthines, the preparation thereof and their use as pharmaceutical compositions
The application relates to new substituted xanthines of general formula wherein R 1 and R 2 are defined as in claims 1 to 11 , the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof, which have valuable pharmacological properties, particularly an inhibiting effect on the activity of the enzyme dipeptidylpeptidase-IV (DPP-IV).
1. A compound of formula (I):
wherein
R 1 denotes a phenylmethyl, phenylprop-2-enyl, pyridinyl-methyl, pyrimidinylmethyl, naphthylmethyl, quinolinylmethyl, 1H-quinolin-2-onyl-methyl, imidazo [1,2-a]quinolinylmethyl, quinazolinylmethyl, 3H-quinazolin-4-onylmethyl, quinoxalinylmethyl, phenanthridinylmethyl, naphthyridinyl-methyl, benzo [1.6]naphthyridinylmethyl, imidazopyridinylmethyl or benzotriazolyl-methyl group which may be substituted in each case by one or two fluorine, chlorine or bromine atoms or one or two cyano, nitro, amino, C 1-3 -alkyl, C 1-3 -alkyloxy, phenyl or morpholinyl groups, while the substituents may be identical or different,
R 2 denotes a cyano-C 1-3 -alkyl, hydroxycarbonylmethyl, C 1-6 -alkyloxycarbonylmethyl, C 3-6 -alkenyloxycarbonylmethyl, C 3-6 -cycloalkyl-C 1-3 -alkyloxycarbonylmethyl or C 3-6 -cycloalkyloxycarbonylmethyl group, while the alkyl, alkenyl and cycloalkyl groups in each case may be substituted by one or two C 1-3 -alkyl or C 1-3 -alkyloxy groups and/or partly or completely fluorinated,
while, unless otherwise stated, the above-mentioned alkyl, alkenyl and alkynyl groups may be straight-chain or branched,
or a tautomer, enantiomer, diastereomer, or a mixture thereof, a prodrug thereof or a salt thereof.
2. The compound according to claim 1 , wherein
R 1 denotes a pyridinylmethyl, pyrimidinylmethyl, quinazolinyl-methyl, quinoxalinylmethyl or naphthylmethyl group which may be substituted by one or two cyano or methyl groups, and
R 2 denotes a cyanomethyl, hydroxycarbonylmethyl, methoxycarbonylmethyl or ethoxycarbonylmethyl group.
3. The compound according to claim 1 , wherein
R 1 denotes a quinazolinylmethyl group which may be substituted by a methyl group, and
R 2 denotes a methyl group substituted by a C 1-4 -alkoxy-carbonyl group.
4. A compound selected from:
(a) 1-(naphthyl-1-ylmethyl)-3-(methoxycarbonylmethyl)-7-(but-2-ynyl)-8-(3-amino-piperidin-1-yl)-xanthine
(b) 1-(naphthyl-1-ylmethyl)-3-(cyanomethyl)-7-(but-2-ynyl)-8-(3-amino-piperidin-1-yl)-xanthine
(c) (R)-1-(4-methyl-quinazolin-2-ylmethyl)-3-(methoxycarbonylmethyl)-7-(but-2-ynyl)-8-(3-amino-piperidin-1-yl)-xanthine
(d) (R)-1-(4-methyl-quinazolin-2-ylmethyl)-3-(ethoxycarbonylmethyl)-7-(but-2-ynyl)-8-(3-amino-piperidin-1-yl)-xanthine
(e) (R)-1-(4-methyl-quinazolin-2-ylmethyl)-3-(hydroxycarbonylmethyl)-7-(but-2-ynyl)-8-(3-amino-piperidin-1-yl)-xanthine or
a tautomer or a salt thereof.
5. A physiologically acceptable salt of a compound according to claim 1 with an inorganic or organic acid or base.
6. A pharmaceutical composition, comprising a pharmaceutically acceptable amount of a compound according to claim 1 together with one or more inert carriers or diluents.
7. A method of treating type II diabetes mellitus or obesity comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 .
8. A method of treating type II diabetes mellitus comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 .
9. A method of treating obesity comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 .
10. The method of claim 7 , wherein the compound is administered to the patient by intravenous route in an amount of 1 to 100 mg or by oral route in an amount of 1 to 1000 mg, in each case 1 to 4 times a day.
11. The method of claim 7 , wherein the compound is administered to the patient by intravenous route in an amount of 1 to 30 mg, or by oral route in an amount of 1 to 100 mg, in each case 1 to 4 times a day.
12. A compound according to claim 1 , wherein:
R 1 denotes a phenylmethyl, phenylprop-2-enyl, pyridinyl-methyl, pyrimidinylmethyl, imidazo [1,2-a]quinolinylmethyl, quinoxalinylmethyl, phenanthridinylmethyl, naphthyridinyl-methyl, benzo [1.6]naphthyridinylmethyl, imidazopyridinylmethyl or benzotriazolyl-methyl group which may be substituted in each case by one or two fluorine, chlorine or bromine atoms or one or two cyano, nitro, amino, C 1-3 -alkyl, C 1-3 -alkyloxy, phenyl or morpholinyl groups, while the substituents may be identical or different.
13. A compound according to claim 1 , wherein:
R 2 denotes a hydroxycarbonylmethyl, ethoxycarbonylmethyl, C 3-6 -alkenyloxycarbonylmethyl, C 3-6 -cycloalkyl-C 1-3 -alkyloxycarbonylmethyl or
C 3-6 -cycloalkyloxycarbonylmethyl group, while the alkyl, alkenyl and cycloalkyl groups in each case may be substituted by one or two C 1-3 -alkyl or C 1-3 -alkyloxy groups and/or partly or completely fluorinated.